N-hydroxyureas as 5-lipoxygenase inhibitors and inhibitors of oxidative modification of low density lipoprotein

Abstract

This invention relates to compounds having 5-lipoxygenase inhibiting properties and inhibition of oxidative modification of low density lipoprotein which have the formula: ##STR1## wherein: R 1 and R 3 are independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, or C 1 -C 6 trifluoroalkoxy; R 2 is hydrogen or methyl; R 4 is hydrogen, methyl or hydroxy; R 5 is hydrogen, --NH 2 , C 1 -C 6 alkyl, aryl, aralkyl, or --N═C(CH 3 ) 2 ; X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. Compounds which inhibit 5-lipoxygenase are useful in the treatment of diseases mediated by leukotrienes such as inflammation or bronchoconstriction. Compounds which inhibit oxidative metabolism of low density lipoprotein are useful in the inhibition of atherosclerotic plaque formation.

What is claimed is: 
     
       1. A compound according to the formula: ##STR11## wherein: R 1  and R 3  are independently hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or C 1  -C 6  trifluoroalkoxy; R 2  is hydrogen or methyl;   R 4  is hydrogen, methyl or hydroxy;   R 5  is hydrogen, --NH 2 , C 1  -C 6  alkyl, C 6  -C 10  aryl, C 6  -C 10  aryl-C 1  -C 6  alkylene, or --N═C(CH 3 ) 2  ;   X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.     
     
     
       2. A compound according to claim 1 which is selected from: 1-hydroxy-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-urea,   1-[3-chloro-4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy)benzyl]-1-hydroxy-urea,   1-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-1-hydroxy-urea   1-hydroxy-1-[3-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-urea,   1-[3-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-1-hydroxy-urea   1-hydroxy-1-[4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzyl]-urea,   1-hydroxy-1-[4-[5-methyl-2-(4-trifluoroethoxy-phenyl)-oxazol-4-ylmethoxy]-benzyl]-urea,   1-hydroxy-1-[1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-ethyl]-urea,   1-hydroxy-1-[4-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-urea,   1-hydroxy-1-[(4-(2-phenyl-thiazol-4-ylmethoxy)-benzyl]-urea,   1-hydroxy-1-[4-[2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzyl]-urea   1-hydroxy-1-[4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-benzyl]-urea,   3-(4-fluorophenyl)-1-hydroxy-1-[4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-benzyl]-urea,   1-[4-[2-(4-chlorophenyl)-thiazol-4-ylmethoxy)-benzyl]-3-hexyl-1-hydroxy-urea,   1-hydroxy-1-[4-[2-(4-methoxyphenyl)-thiazol-4-ylmethoxy]-benzyl]-urea,   1-[4-[2-(4-chlorophenyl)-thiazol-4-ylmethoxy]-benzyl]-1-hydroxy-thiourea,   1-[4-[2-(4-chlorophenyl)-thiazol-4-ylmethoxy)-benzyl]-3-hexyl-1-hydroxy-urea,   1-hydroxy-1-[2-hydroxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-ethyl]urea,   1-hydroxy-4-[4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzyl]semicarbazide,   1-isopropylidine-4-hydroxy-4-[4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzyl]-semicarbazone,   4-hydroxy-4-[4-(2-phenyl-thiazol-4-ylmethoxy)-benzyl]-semicarbazide, and   4-hydroxy-4-[4-(2-phenyl-thiazol-4-ylmethoxy)-benzyl]-semicarbazide hydrochloride.   
     
     
       3. A method of treating inflammation in a mammal which comprises administration thereto a therapeutically effective amount of a cornpound having the formula: ##STR12## wherein: R 1  and R 3  are independently hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or C 1  -C 6  trifluoroalkoxy; R 2  is hydrogen or methyl;   R 4  is hydrogen, methyl or hydroxy;   R 5  is hydrogen, --NH 2 , C 1  -C 6  alkyl, C 6  -C 10  aryl, C 6  -C 10  aryl-C 1  -C 6  alkylene, or --N═C(CH 3 ) 2  ;   X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.     
     
     
       4. A method of treating bronchoconstriction in a mammal which comprises administration thereto a therapeutically effective amount of a compound having the formula: ##STR13## wherein: R 1  and R 3  are independently hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or C 1  -C 6  tfifluoroalkoxy; R 2  is hydrogen or methyl;   R 4  is hydrogen, methyl or hydroxy;   R 5  is hydrogen, --NH 2 , C 1  -C 6  alkyl, C 6  -C 10  aryl, C 6  -C 10  aryl-C 1  -C 6  alkylene, or --N═C(CH 3 ) 2  ;   X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.     
     
     
       5. A method of inhibiting atherosclerotic plaque formation in a mammal which comprises administration thereto a therapeutically effective amount of a compound having the formula: ##STR14## wherein: R 1  and R 3  are independently hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or C 1  -C 6  trifluoroalkoxy; R 2  is hydrogen or methyl;   R 4  is hydrogen, methyl or hydroxy;   R 5  is hydrogen, --NH 2 , C 1  -C 6  alkyl, C 6  -C 10  aryl, C 6  -C 10  aryl-C 1  -C 6  alkylene, or --N═C(CH 3 ) 2  ;   X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.     
     
     
       6. A pharmaceutical composition for the treatment of inflammation or bronchoconstriction or inhibition of atherosclerotic plaque formation which comprises a pharmaceutical carrier and a therapeutically effective amount of a compound having the formula: ##STR15## wherein: R 1  and R 3  are independently hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or C 1  -C 6  trifluoroalkoxy; R 2  is hydrogen or methyl;   R 4  is hydrogen, methyl or hydroxy;   R 5  is hydrogen, --NH 2 , C 1  -C 6  alkyl, C 6  -C 10  aryl, C 6  -C 10  aryl-C 1  -C 6  alkylene, or --N═C(CH 3 ) 2  ;   X and Y are independently O or S; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.